Guillain‐Barré syndrome following COVID‐19 vaccination: An updated systematic review of cases

Key Clinical Message Guillain‐Barré syndrome (GBS) is a rare but possible complication that may occur after COVID‐19 vaccination. In this systematic review, we found that GBS presented in patients with an average age of 58. The average time for symptoms to appear was 14.4 days. Health care providers should be aware of this potential complication. Abstract Most instances of Guillain‐Barré syndrome (GBS) are caused by immunological stimulation and are discovered after vaccinations for tetanus toxoid, oral polio, and swine influenza. In this systematic study, we investigated at GBS cases that were reported after receiving the COVID‐19 vaccination. Based on PRISMA guidelines, we searched five databases (PubMed, Google Scholar, Ovid, Web of Science, and Scopus databases) for studies on COVID‐19 vaccination and GBS on August 7, 2021. To conduct our analysis, we divided the GBS variants into two groups, acute inflammatory demyelinating polyneuropathy and non‐acute inflammatory demyelinating polyneuropathy (AIDP and non‐AIDP), and compared the two groups with mEGOS and other clinical presentation In this systematic review, 29 cases were included in 14 studies. Ten cases belonged to the AIDP variant, 17 were non‐AIDP (one case had the MFS variant, one AMAN variant, and 15 cases had the BFP variant), and the two remaining cases were not mentioned. Following COVID‐19 vaccination, GBS cases were, on average, 58 years of age. The average time it took for GBS symptoms to appear was 14.4 days. About 56 percent of the cases (56%) were classified as Brighton Level 1 or 2, which defines the highest level of diagnostic certainty for patients with GBS. This systematic review reports 29 cases of GBS following COVID‐19 vaccination, particularly those following the AstraZeneca/Oxford vaccine. Further research is needed to assess all COVID‐19 vaccines' side effects, including GBS.


| INTRODUCTION
More than 267 million individuals have been infected with COVID-19, which is spurred on by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and has killed 4.8 million people globally. 1,2 The development of vaccines has been ongoing since the beginning of the pandemic. The vaccines became available worldwide in 2021, which was an early milestone that helped relieve the COVID-19 pandemic. Vaccination was able to slow down the spread of infection, allowing hospitals to heal from an influx of patients during peak incidence. 3 About half of the world's population (55.5%) has received a dose of the COVID-19 vaccine at least once, 8.35 billion doses have been administered worldwide, and 30.58 million doses are administered daily. [4][5][6] Although vaccinations such as those from Pfizer and AstraZeneca are effective and safe, some recipients have reported side effects. 7,8 As a result of taking the vaccine, mild symptoms such as soreness, headaches, fatigue, chills, joint pain, nausea, muscle spasms, sweating, and dizziness may occur. [9][10][11] A few cases of Guillain-Barré Syndrome (GBS) have been reported following vaccination. 12,13 GBS is a rare immune-mediated polyradiculoneuropathy in which the immune system attacks peripheral nerves following infection with a virus or bacteria. GBS has no clearly defined cause, but it may occur after infection with a virus or bacteria. In rare cases, GBS can also be preceded by vaccination. 8 The small risk of GBS associated with the swine influenza vaccine used in 1976-77 suggests this possible causal association. Also, older formulations of the rabies vaccine were found to increase the risk of GBS. It has been suggested that oral polio vaccines and tetanus toxoidcontaining vaccines might cause GBS. Recently, the US Vaccine Adverse Events Reporting System reported an association between GBS and the quadrivalent meningococcal vaccine (MCV4). 14,15 GBS is an autoimmune disorder in which the body's immune system attacks the peripheral nerves. This results in the inflammation and the damage of the nerves which can lead to various affects throughout the body. This can range from numbness to paralysis. 16 We introduce in this systematic review 13 case reports and case series studies, as well as one letter describing confirmed cases of GBS after vaccination against the COVID-19 virus.

| Study design
We conducted a thorough literature review in August 2021 using the terms (("Guillain-Barre Syndrome"[Mesh]) OR "Miller Fisher Syndrome"[Mesh]) AND "COVID-19 Vaccines"[Mesh], TITLE-ABS-KEY (Guillain AND barre AND (COVID-19 AND vaccine*)). We searched PubMed, Google Scholar, Ovid, Web of Science, and Scopus databases for identifying case series and case reports published on August 7, 2021, for COVID-19; Two reviewers separately searched to find the studies that matched the search terms. Studies describing the cases of Guillain Barré Syndrome following COVID-19 vaccination ( Figure 1); in addition, the analysis did not include review articles or consensus statements. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) were used to illustrate inclusions and exclusions [20]. We discovered 113 studies from PubMed, Google Scholar, Ovid, Web of Science, and Scopus based on our search parameters. 95 fulltext publications were evaluated after the exclusion of duplicate studies, studies with incomplete clinical data, review articles, and papers irrelevant to our research purpose. Accordingly, 14 studies of COVID-19 immunization and GBS were examined for descriptive analysis. These 14 articles were included in our evaluation since they satisfied our aforementioned inclusion criteria. (Figure-1).

| Inclusion criteria
The published studies' inclusion criteria included the following: 1. GBS confirmed in post-COVID-19 vaccine recipients by clinical manifestation and diagnostic procedures including EMG and cerebrospinal fluid (CSF) testing.

| Exclusion criteria
The exclusion criteria for the studies include: 1. Individuals who had vaccinations and were diagnosed with a condition other than GBS, such as myopathy, toxin induced polyneuropathy, critical illness polyneuropathy (CIP), or critical illness myopathy. 2. Studies that used repeated instances in duplicate 3. Languages other than English studies. 4. Exclusion of studies without a confirming GBS diagnosis.

| Quality assessment
The overall quality of case series and case reports has been evaluated using the JBI (Joanna Briggs Institute) Critical Appraisal Checklist for Case Reports.

Included
Studies included in quantitative synthesis (meta-analysis=14) ( ) GBS and its variations, such as paraparesis/quadriparesis and cranial nerve deficits, diagnostic tests for SARS-CoV-2 infection, such as RT-PCR nasopharyngeal, and delay between COVID-19 immunization and early signs of GBS.

| Data analysis
For all patients throughout the 14 case reports and series, pooled descriptive analyses were performed to compare the differences between AIDP and Other GBS variations, the two primary categories of GBS variants (comprising of AMSAN, AMAN, BFP, MFS, Polyneuritis cranialis).
Using the chi-square test for categorical covariates and the t-test for continuous covariates, we evaluated the differences between two groups for the variables. Additionally, a sub-analysis of the variations in frequencies and proportions across three groups made up of AIDP and non-AIDP individuals was carried out. The Chi-square test was used in other statistics using IBM SPSS Statistics version 25.

| RESULTS
The study included 29 cases from 14 studies. The GBS variants were divided into two categories (AIDP and non-AIDP). Consequently, 10 of the 27 cases were AIDP, 17 non-AIDP, and two cases lacked data regarding the GBS variant type, so they were not included in the analysis but discussed. We found no statistically significant difference in age between the two groups (p = 0.920). There were 16 males and 11 females in the study, and no differences were observed between the two groups regarding gender (p = 0.373). We detected the difference between the two groups regarding the type of the vaccine. None of the three vaccines showed a significant difference between the two groups concerning the incidence of GBS (Table 1). One patient was previously tested positive for SARS-COV-2 in the non-AIDP group, and all patients in the AIDP group were negative (p = 0.729). one patient in each group was admitted to ICU (p = 0.348). We observed no statistical difference regarding the time from vaccination to onset of GBS between the two groups (p = 0.420) ( Table 2). Protein values ranges were (54-900) and (75-722) in AIDP and non-AIDP, respectively, (p = 0.392). mEGOS score means and standard deviations were (6 ± 5.51) and (10.38 ± 1.06) in AIDP and non-AIDP, respectively; the p-value was significant (p = 0.050), indicating a significant association between non-AIDP and increasing mEGOS score compared to AIDP. Albumino-cytological dissociation was present in 2 patients in the AIDP group and present in 15 patients in the non-AIDP group; p-value was significant (p = 0.000), indicating a significant association between non-AIDP and the presence of Albumino-cytological dissociation compared to AIDP. One patient was mechanically ventilated in the AIDP group, and five patients were mechanically ventilated in the non-AIDP group; the p-value was significant (p = 0.002), and this shows a significant association between the non-AIDP group and increasing mechanical ventilation compared to the AIDP group (Table 1). Brighton criteria level of diagnostic certainty, MRC grade at the upper and lower limb, and predicted probability to walk unaided after 4 weeks, 3 months, and 6 months are classified in the two groups in Table 3.
We found a statistically significant association between AIDP and incidence of general muscle weakness, upper limb weakness, lower limb weakness, quadriparesis, paraplegia, ascending paralysis, numbness, diarrhea, Bell's palsy, and dysphagia (Table 4). On the other hand, we found a significant difference between non-AIDP and incidence of bilateral facial weakness, paresthesia, quadriplegia, headache, visual disturbances, back pain, and diplopia (Table 4).

| DISCUSSION
There has been extensive research into Guillain-Barré syndrome associated with various vaccines available to understand its association with the disease. 32 As a result of our study, we found 14 research articles reporting 29 cases of vaccination against SARS-CoV-2 infection resulting in GBS syndrome. A total of 14 studies were included, of which 13 were case reports and series and one letter. The mean age of the cases that got GBS after receiving COVID-19 vaccination was 58 years old. The details of the studies, including the type of study, country, number of patients, mean age, GBS variant, and type of vaccine, have been tabulated in Table 3. There were two cases from the United States, two from Italy, 12 from the United Kingdom, 10 from India, two from Austria, and one from Qatar (Table 3). An included letter reported 100 cases of GBS from the USA after receiving Johnson & Johnson's first dose. 31 Of the 29 cases, 44.8% were female and 55.2% were male. Out of the 29 cases, 26 received a first dose of AstraZeneca/Oxford vaccine, one received Johnson & Johnson vaccine, and two received Pfizer vaccine. There are several subtypes of GBS based on how it manifests clinically; acute inflammatory demyelinating polyradiculoneuropathy is the most prevalent kind (AIDP). Axonal forms such as acute motor axonal neuropathy (AMAN) and acute motor-sensory axonal neuropathy are among the other categories (AMSAN). Miller Fisher syndrome is a regional form of GBS. A diagnosis of GBS is based on a combination of clinical presentation, CSF analysis (characterized by an increased protein level without pleocytosis), and electrophysiological criteria. The chronic form of GBS is known as chronic inflammatory demyelinating polyneuropathy (CIDP) 33 ; accordingly, 10 patients had AIDP, one MFS, and one AMAN variants, while 15 patients had BFP variants of GBS (Table 3).
Furthermore, we utilized the Brighton criteria for the intensity of diagnosis and the mEGOS score to differentiate the certainty of categorization for GBS variations (14). This criterion is used to provide levels 1-4 of diagnostic certainty based on the patient's clinical presentation, exam results, and diagnostic tests. 14 The Brighton Criteria of diagnostic certainty of GBS was discussed in eight out of the total studies. Seven patients reached Level 1, seven patients reached Level 2, 10 patients reached Level 3, and one patient reached Level 4 of the Brighton Criteria. (Table 5).
Based on a patient's clinical presentation on Day 7 after admission, the modified Erasmus GBS outcome score (mEGOS) is regarded as a crucial prognostic sign that aids in predicting the long-term fate of the patient. Therefore, the likelihood that a patient will not be able to walk independently six months after admission increases with increasing mEGOS score. The mean and standard deviation of mEGOS scores were (6 ± 5.51) and (10.38 ± 1.06) in AIDPs and non-AIDPs, respectively (Table 4). 14 The CSF protein level was elevated in most cases, which is a critical biomarker determining severity and extent of disease. 34 In the AIDP group, there were two cases of albumino-cytological dissociation, whereas in the non-AIDP group, there were 15 cases. One patient in the AIDP group required mechanical ventilation, whereas five patients in the non-AIDP group required mechanical ventilation (Table 4).
Acute GBS presents with proximal and distal weakness as well as significant neck flexion weakness requiring immediate intubation. GBS may also cause areflexia or hyporeflexia. Some patients may also develop dysphagia, facial diplegia, or cranial nerve involvement. 15 Some patients developed general muscle weakness, upper limb weakness, lower limb weakness, quadriparesis, paraplegia, ascending paralysis, numbness, diarrhea, Bell's palsy, and dysphagia ( Table 2). On the other hand, some patients also had bilateral facial weakness, paresthesia, quadriplegia, headache, visual disturbances, back pain, and diplopia. Patients with AIDP variants and non-AIDP variants had numbness in 6 cases and 14 cases, respectively. Nine patients showed a state of Cranial Nerve VII palsy in our review, one of AIDP variant and eight of none AIDP, respectively (Table 4).
Bell's palsy, an autoimmune demyelinating cranial neuritis, is considered to be a mononeuritic variant of GBS, which causes the immune system to attack peripheral nerve myelin antigens. 35 One of the AIDP variants and three non-AIDP GBS patients both presented with Bell's palsy, in which the earliest symptoms include weakness and tingling in the extremities that quickly spread and paralyze the whole body. 13 GBS, characterized by chronic weakness and absent or decreased myotatic reflex, is a group of neuropathic disorders. 12 In patients with the AIDP variant there were five upper limb weakness cases and seven lower limb weakness cases. In contrast, in patients with the non-AIDP variant there were seven upper limb weakness cases and ten lower limb weakness cases.
The latency period between the administration of the vaccine and the appearance of GBS symptoms was 14.41 ± 7.23 days (Table 4). In reality, the delay between the injection of COVID-19 vaccinations and the onset of GBS symptoms offers a hint to the etiology of GBS, which may be explained by the immunological reaction to the COVID-19 vaccines resulting in peripheral nerve injury. 36 Autoantibodies may develop against certain viral components of vaccines that cross-react with peripheral nerves due to molecular mimicry, resulting in immune-mediated damage to the peripheral nervous system leading to GBS. 37 In 28 cases, the PCR test was negative, while in one, it was positive, indicating that the vaccine against SARS-CoV-2 caused GBS, not the COVID-19 disease (Table 5). 38 It is also possible to develop GBS without infection and be negative in RT-PCR, indicating that immune-mediated mechanisms trigger the release of PNS antigens that damage peripheral nerves. 39 The most common treatment was intravenous immunoglobulin, or IVIG, and methylprednisolone for cases 6 and 7. (Table 5), In our cohort, we identified 17 cases in which MRI imaging was performed on the brain. Among these, 7 cases had normal findings, other cases had abnormal findings, and 22 cases had NCS findings (Table 5).

| LIMITATIONS
Our study is one of the first to compare the clinical presentation, management, and outcomes of vaccinated patients who developed GBS, highlighting differences between GBS variants. In addition, we concentrated on Brighton categorization and mEGOS GBS functional rating. It is important to keep in mind various restrictions while evaluating our research. Despite our thorough search, which we believe is sufficient to capture all pertinent case series and reports, the first limitation is that there must be case reports and case series of GBS following COVID-19 vaccine administration. As a result, there is a chance that we will miss out on new upcoming studies. Another limitation is that the patient in study number 11 had GBS after taking the vaccine and catching COVID-19 despite being vaccinated, and we included this study as GBS cause is unclear and not confirmed regarding COVID-19 disease or vaccination. 27 Finally, The last included study reported by FDA was not included in the meta-analysis because of the lack of information about 100 patients who were reported to have GBS after the COVID-19 vaccine because there is a disproportionate number of atypical cases of GBS. 31

| CONCLUSION
In this systematic review, we examined the neurological outcomes and presentations related to the COVID-19 vaccination. To our knowledge, this is the updated study that describes the neurological outcomes associated with GBS after the COVID-19 vaccine. In our review, we included 14 studies with a total of 29 cases, 59% of which were males and 41% were females. Following vaccination, GBS typically appeared 14.4 days later. Most cases developed GBS after receiving the AstraZeneca/Oxford vaccine. Most patients who developed GBS following COVID-19 vaccinations were treated with intravenous immunoglobulins. A large percentage of those included in the study have recovered or are recovering. Our systematic review has concluded that more research is needed to understand the effects of COVID-19 vaccination on the body and its role in the development of GBS.